EFFECT OF CATIONIC POLIMER FORMULATION ON THE IONTOPHORETIC DELIVERY OF DOXORUBICIN

Intruducion: Doxorubicin (DOX) and its bioactive derivates are among the most widely used anticancer drugs in chemotherapy treatment. Due to the various side effects, topical chemotherapy could be an interesting alternative to treat skin cancer with reduced toxicity. Nevertheless, the superficial lipophilic layer of the skin, the stratum corneum, constitutes a major barrier to the cutaneous delivery of hydrophilic and charged molecules such as DOX. The application of iontophoresis, to drive molecules into the skin, can improve DOX skin penetration. Objectives: The aim of this work was to investigate DOX percutaneous absorption and retention in the skin with the application of iontophoresis. The convective flow contribution to the overall electrotransport of DOX was also elucidated for non-ionic gel of hydroxyethylcellulose (HEC) and cationic gel of chitosan. Methods: DOX 0,5% was dispersed in water, HEC and Chitosan gel. All formulations contained 119 mM of NaCl and pH 5.5. Experiments were performed in vitro using vertical, flow-through diffusion cells, dermatomed porcine skin and Ag/AgCl electrodes. DOX transport from anode compartment was followed over a period of 6h at a constant current of 0.5mA/cm2. In addition, so that electroosmotic and electrorepulsive contributions of DOX delivery could be distinguished, the DOX formulations also contained the electroosmotic marker acetominophen, at the same molar concentration as DOX. Results: It was observed that iontophoresis of DOX increased significantly the skin permeation and skin retention of the drug. The electroosmotic flow was dramatically reduced when DOX was added to the non-ionic gel indicating that the drug interacts with negative charges of the skin. Interestingly, electroosmosis was also significantly reduced when the iontophoresis of the chitosan gel, in the absence of DOX, was performed. Consequently, electroosmotic marker transport from this gel almost disappeared when the positively charged drug was added to the cationic gel. Chitosan seems to interact with negative charges of the skin, hence, reducing electroosmotic flow but also releasing DOX from interactions with these sites and thus improving its diffusion to deeper skin layers. Conclusions: Iontophoresis increased significantly not only the permeation, but also the skin retention of DOX. Despite the fact that iontophoresis of chitosan gels decreased significantly the electrosmotic flow, it improved DOX diffusion through deeper layers of the skin, probably by competing with the drug for stratum corneum negative charge sites.